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UCSF UC San Francisco Previously Published Works Title Early, Accurate Diagnosis and Early Intervention in Cerebral Palsy: Advances in Diagnosis and Treatment. Permalink https://escholarship.org/uc/item/3qb3z8f0 Journal JAMA pediatrics, 171(9) ISSN 2168-6203 Authors Novak, Iona Morgan, Cathy Adde, Lars et al. Publication Date 2017-09-01 DOI 10.1001/jamapediatrics.2017.1689 Copyright Information This work is made available under the terms of a Creative Commons Attribution- NonCommercial-ShareAlike License, availalbe at https://creativecommons.org/licenses/by- nc-sa/4.0/ Peer reviewed eScholarship.org Powered by the California Digital Library University of California
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Early, Accurate Diagnosis and Early Intervention in Cerebral Palsy: Advances in Diagnosis and Treatment

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Early, Accurate Diagnosis and Early Intervention in Cerebral PalsyAdvances in Diagnosis and TreatmentTitle Early, Accurate Diagnosis and Early Intervention in Cerebral Palsy: Advances in Diagnosis and Treatment.
Permalink https://escholarship.org/uc/item/3qb3z8f0
Publication Date 2017-09-01
Copyright Information This work is made available under the terms of a Creative Commons Attribution- NonCommercial-ShareAlike License, availalbe at https://creativecommons.org/licenses/by- nc-sa/4.0/ Peer reviewed
eScholarship.org Powered by the California Digital Library University of California
Early, Accurate Diagnosis and Early Intervention in Cerebral Palsy Advances in Diagnosis and Treatment Iona Novak, PhD; Cathy Morgan, PhD; Lars Adde, PhD; James Blackman, PhD; Roslyn N. Boyd, PhD; Janice Brunstrom-Hernandez, MD; Giovanni Cioni, MD; Diane Damiano, PhD; Johanna Darrah, PhD; Ann-Christin Eliasson, PhD; Linda S. de Vries, PhD; Christa Einspieler, PhD; Michael Fahey, PhD; Darcy Fehlings, PhD; Donna M. Ferriero, MD; Linda Fetters, PhD; Simona Fiori, PhD; Hans Forssberg, PhD; Andrew M. Gordon, PhD; Susan Greaves, PhD; Andrea Guzzetta, PhD; Mijna Hadders-Algra, PhD; Regina Harbourne, PhD; Angelina Kakooza-Mwesige, PhD; Petra Karlsson, PhD; Lena Krumlinde-Sundholm, PhD; Beatrice Latal, MD; Alison Loughran-Fowlds, PhD; Nathalie Maitre, PhD; Sarah McIntyre, PhD; Garey Noritz, MD; Lindsay Pennington, PhD; Domenico M. Romeo, PhD; Roberta Shepherd, PhD; Alicia J. Spittle, PhD; Marelle Thornton, DipEd; Jane Valentine, MRCP; Karen Walker, PhD; Robert White, MBA; Nadia Badawi, PhD
IMPORTANCE Cerebral palsy describes the most common physical disability in childhood and occurs in 1 in 500 live births. Historically, the diagnosis has been made between age 12 and 24 months but now can be made before 6 months’ corrected age.
OBJECTIVES To systematically review best available evidence for early, accurate diagnosis of cerebral palsy and to summarize best available evidence about cerebral palsy–specific early intervention that should follow early diagnosis to optimize neuroplasticity and function.
EVIDENCE REVIEW This study systematically searched the literature about early diagnosis of cerebral palsy in MEDLINE (1956-2016), EMBASE (1980-2016), CINAHL (1983-2016), and the Cochrane Library (1988-2016) and by hand searching. Search terms included cerebral palsy, diagnosis, detection, prediction, identification, predictive validity, accuracy, sensitivity, and specificity. The study included systematic reviews with or without meta-analyses, criteria of diagnostic accuracy, and evidence-based clinical guidelines. Findings are reported according to the PRISMA statement, and recommendations are reported according to the Appraisal of Guidelines, Research and Evaluation (AGREE) II instrument.
FINDINGS Six systematic reviews and 2 evidence-based clinical guidelines met inclusion criteria. All included articles had high methodological Quality Assessment of Diagnostic Accuracy Studies (QUADAS) ratings. In infants, clinical signs and symptoms of cerebral palsy emerge and evolve before age 2 years; therefore, a combination of standardized tools should be used to predict risk in conjunction with clinical history. Before 5 months’ corrected age, the most predictive tools for detecting risk are term-age magnetic resonance imaging (86%-89% sensitivity), the Prechtl Qualitative Assessment of General Movements (98% sensitivity), and the Hammersmith Infant Neurological Examination (90% sensitivity). After 5 months’ corrected age, the most predictive tools for detecting risk are magnetic resonance imaging (86%-89% sensitivity) (where safe and feasible), the Hammersmith Infant Neurological Examination (90% sensitivity), and the Developmental Assessment of Young Children (83% C index). Topography and severity of cerebral palsy are more difficult to ascertain in infancy, and magnetic resonance imaging and the Hammersmith Infant Neurological Examination may be helpful in assisting clinical decisions. In high-income countries, 2 in 3 individuals with cerebral palsy will walk, 3 in 4 will talk, and 1 in 2 will have normal intelligence.
CONCLUSIONS AND RELEVANCE Early diagnosis begins with a medical history and involves using neuroimaging, standardized neurological, and standardized motor assessments that indicate congruent abnormal findings indicative of cerebral palsy. Clinicians should understand the importance of prompt referral to diagnostic-specific early intervention to optimize infant motor and cognitive plasticity, prevent secondary complications, and enhance caregiver well-being.
JAMA Pediatr. 2017;171(9):897-907. doi:10.1001/jamapediatrics.2017.1689 Published online July 17, 2017. Corrected on September 5, 2017.
Supplemental content
Author Affiliations: Author affiliations are listed at the end of this article.
Corresponding Author: Iona Novak, PhD, Cerebral Palsy Alliance, The University of Sydney, PO Box 187, Frenchs Forest, New South Wales, Australia 2086 (inovak @cerebralpalsy.org.au).
Clinical Review & Education
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A ccording to a 2007 report, “Cerebral palsy is a group of per- manent disorders of the development of movement and posture, causing activity limitation, that are attributed to
non-progressive disturbances that occurred in the developing fe- tal or infant brain.”1(p9) Cerebral palsy is a clinical diagnosis based on a combination of clinical and neurological signs. Diagnosis typically occurs between age 12 and 24 months.2-4 The following 4 motor types exist but may emerge and change during the first 2 years of life: (1) spasticity (85%-91%); (2) dyskinesia (4%-7%), including dys- tonia and athetosis; (3) ataxia (4%-6%); and (4) hypotonia (2%), which is not classified in all countries.2 Dyskinesia, ataxia, and hy- potonia usually affect all 4 limbs, whereas spasticity is categorized topographically as (1) unilateral (hemiplegia) (38%) and (2) bilat- eral, including diplegia (lower limbs affected more than upper limbs) (37%) and quadriplegia (all 4 limbs and trunk affected) (24%).2 Co- morbidities and functional limitations are common and disabling, in- cluding chronic pain (75%), epilepsy (35%), intellectual disability (49%), musculoskeletal problems (eg, hip displacement) (28%), be- havioral disorders (26%), sleep disorders (23%), functional blind- ness (11%), and hearing impairment (4%).5
Cerebral palsy is the most common physical disability in child- hood, with a prevalence of 2.1 cases per 1000 in high-income countries.6 The prevalence is declining in Australia and Europe.7,8
Exact rates in countries of low to middle income are less certain9 but appear to be higher, with worse physical disability, because of greater infectious disease burden and prenatal and perinatal care differences.10 The complete causal path to cerebral palsy is unclear in approximately 80% of cases, but risk factors are often identifi- able from history taking about conception, pregnancy, birth, and the postneonatal period.11 The full causal path is a complex interplay be- tween several risk factors across multiple epochs,11 including new evidence suggesting that 14% of cases have a genetic component.12-14 Early diagnosis does not preclude further specific etiological investigation, and identifying a specific etiology does not then preclude individuals from also having cerebral palsy. Genetic advances are likely to soon amend the diagnostic process.
Our primary objective was to systematically review best avail- able evidence for early, accurate diagnosis of cerebral palsy. Our sec- ondary objective was to summarize best available evidence about cerebral palsy–specific early intervention that should follow early di- agnosis to optimize neuroplasticity and function.
Methods We conducted a systematic review to develop an international clini- cal practice guideline in accord with the World Health Organiza- tion’s Handbook for Guideline Development15 and the Institute of Medicine’s standards.16 We followed the Equator Network report- ing recommendations outlined in the Appraisal of Guidelines, Re- search and Evaluation (AGREE) II instrument17 and the Preferred Re- porting Items for Systematic Reviews and Meta-analyses (PRISMA) statement.18 We systematically searched MEDLINE (1956-2016), EMBASE (1980-2016), CINAHL (1983-2016), and the Cochrane Li- brary (1988-2016) and hand searched using the following terms: ce- rebral palsy, diagnosis, detection, prediction, identification, predic- tive validity, accuracy, sensitivity, and specificity. We included systematic reviews with or without meta-analyses, criteria of diag-
nostic accuracy, and evidence-based clinical guidelines. Quality was appraised using the Quality Assessment of Diagnostic Accuracy Stud- ies (QUADAS) methodological rating checklist for systematic re- views of diagnostic accuracy.19
The Grading of Recommendations Assessment, Develop- ment, and Evaluation (GRADE) framework was used to assess qual- ity and formulate recommendations along a 4-part continuum, in- cluding strong for, conditional for, conditional against, and strong against.20 As per the GRADE method, we weighed (1) the balance between desirable and undesirable consequences of different man- agement strategies or not acting; (2) family preferences, including benefits vs risks and inconvenience; and (3) cost. Recommenda- tions were discussed face-to-face among all authors, and the manu- script was reviewed, edited, and agreed on by all coauthors. Au- thors were clinicians involved in the diagnosis of cerebral palsy, including neurologists, pediatricians, neonatologists, rehabilita- tion specialists, general practitioners, neuroradiologists, psychia- trists, physical therapists, psychologists, occupational therapists, speech pathologists, nurses, and early educators. Individuals with cerebral palsy and parents also contributed as equal authors, en- suring that recommendations addressed their views and prefer- ences.
Results Six systematic reviews21-26 and 2 evidence-based clinical guidelines27,28 met inclusion criteria. The methodological quality of the evidence was very high (eTable in the Supplement), enabling strong GRADE recommendations.20 Many standardized tools exist that predict risk of cerebral palsy early. Best available evidence was summarized (eTable in the Supplement), and a PRISMA diagram sum- marized study flow (eFigure in the Supplement).
Advances in Diagnosis: Early Clinical Diagnosis Is Now Possible Before age 12 to 24 months was historically regarded as the latent or silent period where cerebral palsy could not be identified accu- rately. Experts now consider the silent period as outdated because
Key Points Question What are the most accurate evaluations for diagnosing cerebral palsy early?
Findings In this systematic review of the literature, we found diagnosis can be accurately made before 6 months’ corrected age. Before 5 months’ corrected age, magnetic resonance imaging plus the General Movements Assessment or the Hammersmith Infant Neurological Examination are recommended; after 5 months’ corrected age, magnetic resonance imaging (where safe and feasible), the Hammersmith Infant Neurological Examination, and the Developmental Assessment of Young Children are recommended.
Meaning Early diagnosis should be the standard of care because contemporary early interventions optimize neuroplasticity and functional outcomes.
Clinical Review & Education Review Early, Accurate Diagnosis and Early Intervention in Cerebral Palsy
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cerebral palsy or “high risk of cerebral palsy” can be accurately pre- dicted before age 6 months’ corrected age.
The 3 tools with best predictive validity for detecting cerebral palsy before 5 months’ corrected age are (1) neonatal magnetic reso- nance imaging (MRI) (86%-89% sensitivity),21,27 (2) the Prechtl Qualitative Assessment of General Movements (GMs) (98% sensitivity),21 and (3) the Hammersmith Infant Neurological Exami- nation (HINE) (90% sensitivity)25 (eTable in the Supplement). Af- ter 5 months’ corrected age, the most predictive tools for detect- ing risk are MRI (86%-89% sensitivity) (where safe and feasible), the HINE (90% sensitivity), and the Developmental Assessment of Young Children (83% C index). High-quality evidence also indi- cates that a trajectory of abnormal GMs or HINE scores, in combi- nation with abnormal MRI, producing congruent findings, is even more accurate than individual clinical assessments in isolation.21,25
To make an early clinical diagnosis before 6 months’ corrected age, a combination of assessments with strong predictive validity coupled with clinical reasoning is recommended. We have made 12 recommendations from best available evidence (Table 1). A highly experienced clinical team should ideally conduct and interpret the standardized assessments and then communicate the news com- passionately.
Interim High Risk of Cerebral Palsy Clinical Diagnosis When the clinical diagnosis is suspected but cannot be made with certainty, we recommend using the interim clinical diagnosis of high risk of cerebral palsy until a diagnosis is confirmed. We rec- ommend specifying cerebral palsy because infants with cerebral palsy require and benefit from different early interventions than infants “at risk of developmental delay,” “at risk of autism,” “at risk of harm,” or with “social risk.” When the infant is perceived to be at risk of cerebral palsy, he or she should be referred for cerebral palsy–specific early intervention (see the Advances in Treatment section), with regular medical, neurological, and developmental monitoring from the infant’s pediatrician or neurologist to assist with forming a diagnostic picture. To assign the interim clinical diagnosis of high risk of cerebral palsy, the infant must have motor dysfunction (essential criterion) and at least one of the other 2 additional criteria.
Essential Criterion (Required) Motor Dysfunction In motor dysfunction, the infant’s quality of movement is reduced (eg, absent fidgety GMs)29 or neurologically abnormal (eg, early ob- servable hand asymmetry or suboptimal HINE scores).30 In addi- tion, the infant’s motor activities may be substantially below those expected for chronological age (eg, abnormal score on a standard- ized motor assessment or parent and caregiver or clinical observa- tions of head lag, not sitting, inability to grasp, or not reaching for a toy when appropriate).
As a caveat, in milder presentations, especially unilateral cere- bral palsy, it is possible for an infant to score within the normal range on a standardized motor assessment, while still displaying abnor- mal movements. For example, an infant with hemiplegia might ob- tain a normal fine-motor score but complete the assessment one- handed. Similarly, an infant with diplegia may achieve normal upper limb scores and abnormal lower limb scores, producing a combined total motor score within the normal range. Therefore, it is essential
that assessments be carried out by a professional skilled at deter- mining atypical movement from variation in typical movement.
Additional Criteria (at Least One Required) Abnormal Neuroimaging Abnormal MRI21,27 with or without serial cranial ultrasound in pre- term infants21,28 may identify neuroanatomical abnormalities pre- dictive of cerebral palsy. The most predictive patterns are (1) white matter injury (cystic periventricular leukomalacia or periventricu- lar hemorrhagic infarctions) (56%), (2) cortical and deep gray mat- ter lesions (basal ganglia or thalamus lesions, watershed injury [para- sagittal injury], multicystic encephalomalacia, or stroke) (18%), and (3) brain maldevelopments (lissencephaly, pachygyria, cortical dys- plasia, polymicrogyria, or schizencephaly) (9%).
Clinical History Indicating Risk for Cerebral Palsy Preconception risks include history of stillbirths, miscarriages, low socioeconomic status, assisted reproduction, and abnormal ge- netic copy number variations.
Pregnancy risks include genetics, birth defects, multiples, males, maternal thyroid disease or preeclampsia, infection, intrauterine growth restriction, prematurity, and substance abuse.
Perinatal birth risks include acute intrapartum hypoxia- ischemia, seizures, hypoglycemia, jaundice, and infection.
Postneonatal risks include stroke, infection, surgical complica- tions, and accidental and nonaccidental brain injury31 occurring be- fore age 24 months, as per the Surveillance of Cerebral Palsy Eu- rope and Australian Cerebral Palsy Register inclusion criteria.
Two Early Detection Pathways Based on Different Risks Half of all infants with cerebral palsy have high-risk indicators iden- tifiable in the newborn period, enabling early screening31 (eg, pre- maturity, atypical intrauterine growth, encephalopathy, genetic ab- normalities, and seizures). We have described this population as having “newborn-detectable risks for cerebral palsy,” and this path- way occurs before 5 months’ corrected age. For the other half of all infants with cerebral palsy, the pregnancy and labor may have ap- peared to be uneventful,31 and parents, caregivers, or community- based professionals first notice delayed motor milestones (eg, not sitting at 9 months or hand asymmetry). This finding may be espe- cially true for infants with unilateral cerebral palsy, who often mas- ter early rudimentary motor skills, such as smiling, swallowing, and head control, and it is not until they attempt more complex motor skills, such as grasp, that asymmetries become observable. We have described this population as having “infant detectable risks for ce- rebral palsy,” and this pathway occurs after 5 months’ corrected age. We developed a conceptual framework for early diagnosis based on these 2 pathways to ensure that the most sensitive and specific tools are used to reduce false-positive and false-negative results. The clini- cal diagnostic pathway algorithm for these 2 groups varies because the tools have different psychometric properties depending on the infant’s age (Figure).
Determining Severity Parents or caregivers will want to learn about the severity of their infant’s physical disability to understand his or her capabilities to plan their future. In infants younger than 2 years, motor severity is diffi- cult to accurately predict for the following reasons: (1) almost half
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Recommendations Strength of Recommendations and Quality of Evidence
1.0 The clinical diagnosis of CP can and should be made as early as possible so that: • The infant can receive diagnostic-specific early intervention and surveillance to optimize neuroplasticity and prevent complications • The parents can receive psychological and financial support (when available)
Strong recommendation based on moderate-quality evidence for infant and parent outcomes
1.1 When the clinical diagnosis is suspected but cannot be made with certainty, the interim clinical diagnosis of high risk of CP should be given so that: • The infant can receive diagnostic-specific early intervention and surveillance to optimize neuroplasticity and prevent complications • The parents can receive psychological and financial support (when available) • Ongoing diagnostic monitoring can be provided until a diagnosis is reached
Strong recommendation based on moderate-quality evidence for infant and parent outcomes
2.0 Early standardized assessments and investigations for early detection of CP should always be conducted in populations with newborn-detectable risks (ie, infants born preterm, infants with neonatal encephalopathy, infants with birth defects, and infants admitted to the NICU)
Strong recommendation based on high-quality evidence of test psychometrics
Early Detection of CP Before 5 mo CA
3.0 Option A: The most accurate method for early detection of CP in infants with newborn-detectable risks and younger than 5 mo (CA) is to use a combination of a standardized motor assessment and neuroimaging and history taking about risk factors
Strong recommendation based on high-quality evidence of test psychometrics in newborn-detectable risk populations
Standardized motor assessment 3.1 Test: GMs to identify motor dysfunction (95%-98% predictive of CP), combined with neuroimaging
Strong recommendation based on high-quality evidence of test psychometrics in newborn-detectable risk populations
Neuroimaging 3.2 Test: MRI (before sedation is required for neuroimaging) to detect abnormal neuroanatomy in the motor areas of the brain (80%-90% predictive of CP). Note that normal neuroimaging does not automatically preclude the diagnosis of risk of CP
Strong recommendation based on high-quality evidence of test psychometrics in newborn-detectable risk populations
4.0 Option B: In contexts where the GMs assessment is not available or MRI is not safe or affordable (eg, in countries of low to middle income), early detection of CP in infants with newborn-detectable risks and younger than 5 mo (CA) is still possible and should be carried out to enable access to early intervention
Strong recommendation based on moderate-quality evidence of test psychometrics in newborn-detectable risk populations
Standardized neurological assessment 4.1 Test: HINE (scores <57 at 3 mo are 96% predictive of CP)
Strong recommendation based on moderate-quality evidence of test psychometrics in newborn-detectable risk populations
Standardized motor assessment 4.2 Test: TIMP
Conditional recommendation based on low-quality evidence of test psychometrics in at-risk populations
Early Detection of CP After 5 mo CA
Accurate early detection of CP in those with infant-discernible risks and age 5-24 mo can and should still occur as soon as possible, but different diagnostic tools are required
5.0 Any infant with: (a) Inability to sit independently by age 9 mo, or (b) Hand function asymmetry, or (c) Inability to take weight through the plantar surface (heel and forefoot) of the feet should receive standardized investigations for CP
Strong recommendation based on high-quality evidence of motor norms
6.0 Option A: The most accurate method for early detection of CP in those with infant detectable risks older than 5 mo (corrected for prematurity) but younger than 2 y is to use a combination of a standardized neurological assessment, neuroimaging, and a standardized motor assessment with a history taking about risk factors
Conditional recommendation based on moderate-quality evidence of test psychometrics in newborn-detectable risk populations
Standardized neurological assessment 6.1 Test: HINE (90% predictive of CP). Those with HINE scores <73 (at 6, 9, or 12 mo) should be considered at high risk of CP. HINE scores <40 (at 6, 9, or 12 mo) almost always indicate…